腺苷在癫痫发病机制中的作用以及腺苷相关癫痫治疗的研究进展

癫痫是慢性反复发作性的脑功能失调综合征,近年来,关于星形胶质细胞及腺苷和癫痫关系的研究逐渐成为热点。腺苷在中枢神经系统中广泛存在,其可以作为整合中枢兴奋性以及抑制性神经递质的调节因子,其诸多生理作用都是通过受体介导实现的。研究腺苷通过星形胶质细胞及腺苷激酶、谷氨酸、表观遗传基因修饰、伽马氨基丁酸受体等通路在抑制癫痫发病机制中的作用,将为治疗癫痫提供全新的治疗思路和措施。本文将针对腺苷抑制癫痫发生的机制以及目前与腺苷有关的癫痫治疗方法进行综述。如果在今后的研究工作中能够进一步明确腺苷在抑制癫痫中的作用机制,就有可能寻找新的干预靶点,对发展新的预防措施,指导预防药物研发,都具有重要意义。     

生长抑素与惊厥

生长抑素(somatostatin,SS)是一种脑肠肽,广泛存在于中枢神经系统和胃肠道组织中,在中枢神经系统中具有神经递质或神经调质的作用。实验证明,它与惊厥的发生有关、但对其作用机制的看法尚有争论。     

一氧化氮的病理及生理作用

许多研究表明,NO是一重要的细胞内信使和新的神经递质,又是效应分子,它介导并调节多种生理功能,在心血管系统,神经系统,炎症和免疫反应中起着重要的作用,NO产生异常和L－Arg-NO途径异常时,可能与某些疾病的发生,发展有一定的关系。     

发现一种新神经递质:内皮-衍生松弛素

最近,科学家们发现,人体内有一种特殊的神经递质,它作用于脑血管内皮细胞和血管平滑肌细胞,具有一定的血管生理学意义。心血管学家称之为内皮—衍生松弛素(EDRF)。在血管系统中,EDRF是内皮细胞在血管舒张药,如乙酰胆碱、缓激肽和组织胺作用下释放的一种局部激素。EDRF扩散到血管平滑肌,通过活化鸟苷酸环化酶(GMP)引起血管扩张,同时使环鸟苷酸腺苷(cGMP)水平增加。多年来人们认为,中枢神经系统中兴奋性神经递质谷氨酸能触发cGMP的大量增加,特别是在cGMP转化率低的小脑中。     

一氧化氮与神经血管单元的关联性及相关药物研究进展

一氧化氮（NO）作为一种重要的信号分子,对中枢神经系统具有重要影响。神经血管单元是近年来提出的从整体上描述中枢神经 系统的新概念,NO对中枢系统的作用是多层次多角度的,NO与神经血管单元这个整体及其各组成单元均密切相关。综述NO及其合成酶 的功能,在中枢神经系统疾病中NO与神经血管单元的相互作用关系及以NO信号通路为靶点的相关药物研究进展。     

多巴胺受体与谷氨酸NMDA受体/A型γ-氨基丁酸受体的相互作用

A型γ-氨基丁酸受体(type Aγ-aminobutyric acid receptor,GABAA_R)和N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR)分别是中枢神经系统中主要的抑制性和兴奋性受体。共同表达在突触区的受体之间在功能上相互调节、相互影响,即受体相互作用。中枢神经系统中GABA_AR和NMDAR之间既可表现为相互抑制,也可表现为相互增强,受体相互作用的深层次机制尚不明确,目前认为可能的机制有:(1)通过第二信使作用;(2)通过受体转运作用;(3)受体间直接接触作用;(4)通过第三方受体介导的作用等。多巴胺是大脑中含量最丰富的儿茶酚胺类神经递质,其相应的受体,多巴胺受体(dopamine receptor,DR)可以激活多种信号转导途径。DR分别与NMDAR/GABA_AR的相互作用已有不少报道,然而由受体介导受体相互作用的机制仍鲜有研究,提示研究中枢神经系统中DR介导NMDAR与GABAA_R相互作用具有非常重要的意义。本文就DR与NMDAR、GABAA_R相互作用的相关机制及研究进展作一综述,以期为进一步阐明DR介导的NMDAR与GABAA_R相互作用提供基础参考。     

中枢神经系统中的心房利钠多肽

放射免疫及免疫组织化学等方法显示:大鼠中枢神经系统广泛存在心房利钠多肽样免疫活性物质,其密度以下丘脑和隔区最高。中枢神经系统中的某些神经元可能在核周体合成心房利钠多肽,参与水、电解质平衡以及心血管活动等多种生理功能的中枢调节过程。提示心房利钠多肽可能既是一种激素,又是中枢神经系统一种新的肽类神经递质或调节因子。     

NMDA受体与Ⅰ组代谢型谷氨酸受体的相互作用

谷氨酸是哺乳动物中枢神经系统重要兴奋性神经递质,参与学习、记忆、药物依赖成瘾及神经系统退行性疾病等多种病理生理过程。谷氨酸通过激活离子型（iGluRs）和代谢型谷氨酸受体（mGluRs）发挥作用。业已有研究提示iGluRs和mGluRs之间存在相互作用,但具体机制尚待阐明。本文从蛋白分子结构、突触可塑性、相互作用可能涉及的信号分子和通路等方面综述了NMDAR与Ⅰ组mGluRs之间的相互作用,旨在为深入研究谷氨酸受体之间的相互作用提供线索。     

促甲状腺激素释放激素的分布及生理作用

促甲状腺激素释放激素(TRH)广泛分布于中枢神经系统和某些外周器官中,它除了有促进垂体前叶释放TSH和PRL等内分泌作用外,作为神经递质或神经调质,对中枢神经系统还可产生广泛的生理效应。     

内源性硫化氢在中枢神经系统中的作用研究进展

硫化氢是继NO和CO之后发现的又一种新的气体信号分子,其被认为是一种神经递质,在中枢神经系统中起着重要的作用。内源性H2S主要由胱硫醚-β合酶(CBS)和胱硫醚γ-裂解酶(CSE)合成,其不仅可以直接作用于中枢神经系统发挥作用,还能通过抗氧化、调节神经内分泌及脑血管功能,进而间接影响中枢神经系统功能,具有广泛的生理作用。近年来,越来越多的研究发现内源性H2S在AD、热惊厥、PD、脑卒中、缺血再灌注脑损伤及遗传性疾病脑损害等神经系统疾病的发病过程中也起着重要作用。本文简要介绍H2S的生化和生理特点,并总结其在中枢神经系统中作用的进展。     

Adenosine receptors interacting proteins (ARIPs): Behind the biology of adenosine signaling

Adenosine is a well known neuromodulator in the central nervous system. As a consequence, adenosine can be beneficial in certain disorders and adenosine receptors will be potential targets for therapy in a variety of diseases. Adenosine receptors are G protein-coupled receptors, and are also expressed in a large variety of cells and tissues. Using these receptors as a paradigm of G protein-coupled receptors, the present review focus on how protein-protein interactions might contribute to neurotransmitter/neuromodulator regulation, based on the fact that accessory proteins impinge on the receptor/G protein interaction and therefore modulate receptor functioning. Besides affecting receptor signaling, these accessory components also play a key role in receptor trafficking, internalization and desensitization, as it will be reviewed here. In conclusion, the finding of an increasing number of adenosine receptors interacting proteins, and specially the molecular and functional integration of these accessory proteins into receptorsomes, will open new perspectives in the understanding of particular disorders where these receptors have been proved to be involved.     

Plasticity of purine release during cerebral ischemia: clinical implications?

Adenosine is a powerful modulator of neuronal function in the mammalian central nervous system. During a variety of insults to the brain, adenosine is released in large quantities and exerts a neuroprotective influence largely via the A₁ receptor, which inhibits glutamate release and neuronal activity. Using novel enzyme-based adenosine sensors, which allow high spatial and temporal resolution recordings of adenosine release in real time, we have investigated the release of adenosine during hypoxia/ischemia in the in vitro hippocampus. Our data reveal that during the early stages of hypoxia adenosine is likely released per se and not as a precursor such as cAMP or an adenine nucleotide. In addition, repeated hypoxia results in reduced production of extracellular adenosine and this may underlie the increased vulnerability of the mammalian brain to repetitive or secondary hypoxia/ischemia.     

Adenosine receptor expression in the adult zebrafish retina

Purinergic Signalling - Adenosine is an endogenous nucleoside in the central nervous system that acts on adenosine receptors. These are G protein-coupled receptors that have four known subtypes:...     

Purinergic signaling in oligodendrocyte development and function

Myelin, an insulating membrane that enables rapid action potential propagation, is an essential component of an efficient, functional vertebrate nervous system. Oligodendrocytes, the myelinating glia of the central nervous system (CNS), produce myelin throughout the CNS, which requires continuous proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Because myelination is essential for efficient neurotransmission, researchers hypothesize that neuronal signals may regulate the cascade of events necessary for this process. The ability of oligodendrocytes and oligodendrocyte progenitor cells to detect and respond to neuronal activity is becoming increasingly appreciated, although the specific signals involved are still a matter of debate. Recent evidence from multiple studies points to purinergic signaling as a potential regulator of oligodendrocyte development and differentiation. Adenosine triphosphate (ATP) and its derivatives are potent signaling ligands with receptors expressed on many populations of cells in the nervous system, including cells of the oligodendrocyte lineage. Release of ATP into the extracellular space can initiate a multitude of signaling events, and these downstream signals are specific to the particular purinergic receptor (or receptors) expressed, and whether enzymes are present to hydrolyze ATP to its derivatives adenosine diphosphate and adenosine, each of which can activate their own unique downstream signaling cascades. This review will introduce purinergic signaling in the CNS and discuss evidence for its effects on oligodendrocyte proliferation, differentiation, and myelination. We will review sources of extracellular purines in the nervous system and how changes in purinergic receptor expression may be coupled to oligodendrocyte differentiation. We will also briefly discuss purinergic signaling in injury and diseases of the CNS.

     

Adenosine receptors in the central nervous system: relationship to the central actions of methylxanthines

Adenosine has a significant role in many functions of the central nervous system. Behaviorally, adenosine and adenosine analogs have marked depressant effects. Electrophysiologically, adenosine reduces spontaneous neuronal activity and inhibits transsynaptic potentials $\text{via}$ interaction with extracellular receptors. Biochemically, adenosine inhibits adenylate cyclase $\text{via}$ a “high” affinity receptor, and activates adenylate cyclase $\text{via}$ a “low” affinity receptor. These receptors, called “A₁” and “A₂” respectively, show differing profiles for activation by adenosine analogs. Radioactive N⁶-cyclohexyladenosine binds selectively to the “high” affinity receptor. One major class of antagonists is known at adenosine receptors: the alkylxanthines, including caffeine and theophylline. Radioactive 1,3-diethyl-8-phenylxanthine, a particularly potent antagonist, appears to bind to both low and high affinity adenosine receptors. Behavioral, electrophysiological, and biochemical effects of alkylxanthines are consistent with the hypothesis that the central stimulatory actions of caffeine and theophylline are due in large part to antagonism of central adenosine receptors.     

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

Nitric oxide (NO) and reactive oxygen species (ROS) play important roles in blood pressure regulation via the modulation of the autonomic nervous system, particularly in the central nervous system (CNS). In general, accumulating evidence suggests that NO inhibits, but ROS activates, the sympathetic nervous system. NO and ROS, however, interact with each other. Our consecutive studies and those of others strongly indicate that an imbalance between NO bioavailability and ROS generation in the CNS, including the brain stem, activates the sympathetic nervous system, and this mechanism is involved in the pathogenesis of neurogenic aspects of hypertension. In this review, we focus on the role of NO and ROS in the regulation of the sympathetic nervous system within the brain stem and subsequent cardiovascular control. Multiple mechanisms are proposed, including modulation of neurotransmitter release, inhibition of receptors, and alterations of intracellular signaling pathways. Together, the evidence indicates that an imbalance of NO and ROS in the CNS plays a pivotal role in the pathogenesis of hypertension.     

Liquid chromatographic-fluorimetric method for the estimation of nitric oxide biosynthesis in the central nervous system

Some amino acids are involved in the biosynthesis of nitric oxide (NO), which has a physiological and pathophysiological role. To study NO biosynthesis, we compared arginine and citrulline levels in the cerebrospinal fluid (CSF) from patients with infectious and/or inflammatory processes within the central nervous system (CNS), with those from patients without those disorders. Arginine concentration was not significantly different between the groups (P = 0.115), whereas citrulline was significantly elevated in the first group (P = 0.020). We propose a simple chromatographic method to estimate NO biosynthesis ex vivo within the CNS, that may be applicable for the study of neurodegenerative and psychiatric diseases such as Parkinson's disease and schizophrenia.     

Fibroblast growth factor 2 upregulates ecto-5′-nucleotidase and adenosine deaminase via MAPK pathways in cultured rat spinal cord astrocytes

Purinergic Signalling - Adenosine triphosphate (ATP) and adenosine are neurotransmitters and neuromodulators in the central nervous system. Astrocytes regulate extracellular concentration of...